The long term objective of this research program remains the analysis of the developmental consequences of trisomy 16 (Ts16) in the mouse central nervous system Genetic homology between the distal part of the long arm of mouse chromosome 16 (MMU 16) and that portion of human chromosome 21 (HSA 21) which produces Down Syndrome (DS) when present in triplicate has led to studies of the Ts16 mouse as a mod, system for analyzing the ontogenesis of central nervous system deficits observed in DS. including those associated with Alzheimer's Disease AD). All DS individuals who live into the fourth decade invariably develop the neuropathologic stigmata of AD.
The specific aim of this research proposal is to examine the ontogenesis and fatal neurons utilizing the peptide somatostatin (SMST) as their neurotransmitter. SMST exerts profound functional effects on cells throughout the body during development. Its mechanism of action is mediated through alteration of transmembrane signalling systems involving cAMP and cGMP as second messengers. In the CNS, neuron populations expressing SMST have been well defined in normal individuals and appear to be """"""""at risk"""""""" in AD, since selective degeneration of both cholinergic and SMST neurons occurs, and SMST immunoreactivity is associated with senile plaques in selected region of the neuraxis. The gene encoding proprosomatostatin (Smst) is located on MMU 16, and regulation of its level of expression appears to be affected by the mutation dwarf (dw), also localized to MMU 16. This mutation is associated with elevated levels of SMST during the development of central and peripheral tissues in homozygous dw mice. The exaggerated levels of SMST that occur in Ts16 mice may contribute the deficits in cholinergic and catecholaminergic development that we have observed in Ts16 mice, and to the deficits in cholinergic and interneuronal function that have observed in murine chimeras composed in part of Ts16 cells. We will use immunocytochemical, in situ hybridization, and ligand autoradiographic procedures to quantify the location and distribution of SMST and its receptor during development sections derived from whole Ts16 and normal littermate fetuses from day 10 through 18 gestation. We will examine the brains of aging Ts16 chimeric mice to determine whether senile plaques and neurofibrillary tangles are present in selected regions the of the neuraxis or whether degenerative structures physically different from plaques a tangles are immunoreactive to SMST.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD019932-05
Application #
3317602
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1984-07-01
Project End
1991-12-31
Budget Start
1990-01-01
Budget End
1991-12-31
Support Year
5
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Berger-Sweeney, J; McPhie, D L; Arters, J A et al. (1999) Impairments in learning and memory accompanied by neurodegeneration in mice transgenic for the carboxyl-terminus of the amyloid precursor protein. Brain Res Mol Brain Res 66:150-62
Hopkins, K J; Oster-Granite, M L (1998) Characterization of N-methyl-d-aspartate receptors in the hyperammonemic sparse fur mouse. Brain Res 797:209-17
Hopkins, K J; McKean, J; Mervis, R F et al. (1998) Dendritic alterations in cortical pyramidal cells in the sparse fur mouse. Brain Res 797:167-72
Oster-Granite, M L; McPhie, D L; Greenan, J et al. (1996) Age-dependent neuronal and synaptic degeneration in mice transgenic for the C terminus of the amyloid precursor protein. J Neurosci 16:6732-41
Neve, R L; Boyce, F M; McPhie, D L et al. (1996) Transgenic mice expressing APP-C100 in the brain. Neurobiol Aging 17:191-203
Robinson, M B; Hopkins, K; Batshaw, M L et al. (1995) Evidence of excitotoxicity in the brain of the ornithine carbamoyltransferase deficient sparse fur mouse. Brain Res Dev Brain Res 90:35-44
Capone, G T; Bendotti, C; Oster-Granite, M L et al. (1991) Developmental expression of the gene encoding growth-associated protein 43 (Gap43) in the brains of normal and aneuploid mice. J Neurosci Res 29:449-60
Fisher, S; Gearhart, J D; Oster-Granite, M L (1991) Expression of the amyloid precursor protein gene in mouse oocytes and embryos. Proc Natl Acad Sci U S A 88:1779-82
Colton, C A; Yao, J; Taffs, R E et al. (1991) Abnormal production of interleukin-1 by microglia from trisomy 16 mice. Neurosci Lett 132:270-4
Grausz, H; Richtsmeier, J T; Oster-Granite, M L (1991) Morphogenesis of the brain and craniofacial complex in trisomy 16 mice. Prog Clin Biol Res 373:169-88

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